As the initial interface between hormone and target tissue the GnRH receptor assumes a central role in control of gonadotroph activity. Therefore, the mechanisms that regulate GnRH receptor concentration in anterior pituitary tissue must be defined before exogenous GnRH and GnRH analogs can be effectively applied toward treatment of pathologies of human reproduction. A hypothesis is presented that suggests that GnRH receptor concentration in anterior pituitary tissue represents a dynamic equilibrium between receptor synthesis and receptor internalization and degradation. This equilibrium can be shifted to favor one or the other of these opposing processes by gonadal steroids and GnRH itself. A series of experiments is proposed to test this postulate. The mechanism and site of action of estradiol will be determined in ewes passively immunized against GnRH. Gonadotroph function in these animals will be reinstated by pulsatile stimulation with a GnRH analog that does not crossreact with the anti-GnRH sera. The hypothalamic and/or hypophyseal loci of estradiol action will be defined and the direct effect of estradiol on GnRH receptor concentration will be evaluated. The relationship between GnRH receptor dynamics and gonadotroph responsiveness during the periovulatory period will be studied in proestrous hamsters. Endogenous GnRH secretion during the morning of proestrus will be blocked with phenobarbital and the effects on receptor dynamics and responsiveness will be monitored. In the third phase of the proposed work GnRH receptor dynamics and gonadotroph responsiveness will be examined during continuous GnRH stimulation and after release from that stimulus. In addition, pituitary function and receptor change during low level continuous GnRH will be determined. In the last phase of this research the temporal pattern of internalization of the hormone-receptor complex will be examined in ovine anterior pituitary cells in culture. This cell culture system will also be employed to further examine the direct effects of estradiol on pituitary responsiveness and GnRH receptor concentration. It is hoped that the information gained from this research will lead to more rational use of GnRH and GnRH analogs for control of fertility in humans and domestic animals.